Conversaciones sobre Neuromedicina: Timing of ER stress generation and how to boost the response in Huntington’s disease

Conversaciones sobre Neuromedicina: Timing of ER stress generation and how to boost the response in Huntington’s disease

Gerardo Lederkremer Ph.D., Full Professor at The Shmunis School of Biomedicine and Cancer Research

Abstract

In Huntington’s disease (HD), protein misfolding and aggregation lead to endoplasmic reticulum (ER) stress and cytotoxicity, similar to other neurodegenerative diseases like Parkinson’s and Alzheimer’s.  Growing evidence, including our research, indicates that this occurs at early stages, through soluble oligomeric forms, before large aggregates develop. To better understand when ER stress is induced during mutant huntingtin (mHtt) aggregation, we employed TET-inducible expression of WT and mutant Htt exon 1 linked to fluorescent proteins. We then used novel optical sorting techniques (pulse-shape FACS) combined with RNAseq analysis, which allowed us to identify early ER stress-induced genes. These could lead to therapeutic targets that may also be relevant to other neurodegenerative diseases.

To try to improve the physiological response to ER stress, we developed a small molecule, MK-28, which restored homeostasis in HD models by specifically activating PKR?like ER kinase (PERK). PERK activation increases eIF2aphosphorylation, which in turn inhibits protein translation, reducing accumulation of damaged proteins in the cell. This activation boosts the unfolded protein response (UPR), thereby reducing ER stress. MK-28 – treatment of the aggressive R6/2 HD mouse model showed significant improvement in their motor performance, physiologicmeasurements and survival, suggesting that PERK activation postpones the appearance of HD symptoms. Boosting of PERK activity could be a new potential therapy for HD, and conceivably open a new approach for recovery of protein homeostasis breakdown in other neurodegenerative diseases.

? Fecha: Viernes 08 de marzo
? Hora: 12:00 – 13:00
? Lugar: Sala Seminarios CEMC Bloque B, Primer Piso, Facultad de Medicina, Universidad de Chile.